Inhalation has become the primary route of administration in the treatment of asthma. This is because, besides providing direct access to the lungs, medication delivered through the respiratory tract provides rapid and predictable onset of action and requires lower dosages compared to the oral route. Typical delivery systems for inhalable drugs are the pressurized metered-dose inhaler (pMDI) comprising a suspension of fine drug particles in a propellant gas, and the dry powder inhaler (DPI) comprising fine drug particles as dry powder typically admixed with coarser excipient such as lactose.
There have been recent advances in the treatment of asthma resulting from the recognition that asthma is a chronic inflammatory disease. Current asthma drugs can be classified into two classes, namely anti-inflammatory agents and bronchodilators. Anti-inflammatory drugs do not relieve asthma symptoms once they occur, rather they are used to control the inflammation. One of the drawbacks of anti-inflammatory drugs is that their onset of action is relatively slow. Therefore, patients often do not recognise any immediate therapeutic effects and tend to stop the medication. This could cause the inflammation uncontrollable. On the other hand, bronchodilators are effective to relieve acute asthma symptoms. They have a potent bronchodilating activity and rapid onset of action.
A particularly advantageous group of anti-inflammatory agents is anti-inflammatory glucocorticosteroids, such as beclomethasone and budesonide.
A particularly advantageous group of bronchodilators is β2-agonists. The short-acting inhaled β2-agonists e.g. salbutamol and terbutaline, are important for an immediate symptomatic asthma relieve, while long-acting β2-agonists, e.g. salmeterol, formoterol and procaterol, are important for the treatment of moderate and severe asthma However, there are currently debates on the safety of a regular use of β2-agonists as well as efficiency of long-acting β2-agonists. Also, the short-acting nature of the drug requires more frequent drug administrations, which tend to cause patient compliance problem.
To overcome these problems, inhalation compositions comprising a combination of a bronchodilator agent and an anti-inflammatory glucocorticosteroid, have been proposed as described e.g. in patent publications EP 0416950, EP 0416951, WO 93/11773 and WO 98/15280. Such combinations include salmeterol with beclomethasone dipropionate, salmeterol with fluticasone propionate, and formoterol with budesonide. These patent publications disclose a method of mixing mechanically the two drug powders and optionally the carrier material in a certain proportion and placing the resulting inhalation powder into an inhaler device. When these combinations are used in dry powder inhalers, the consistency of drug proportion in each dose cannot be easily controlled. The ratio of drugs in each dose significantly depends on the forces existing in each drug, between the drugs, between the drug and carrier material, and between the drug and the dry powder container of the inhaler device. It is well acknowledged that the current powder manufacturing methods, especially the conventional methods, produce dry powder that is highly charged and therefore very cohesive. Hence, it is not easy to maintain the ratio of the drugs in each dose constant. The inconsistency of the dose could cause serious problems especially when a very potent drug is delivered in a much higher amount than expected.
A method for the preparation of inhalation particles by spray-drying a solution of one or several drugs has been disclosed in U.S. Pat. No. 4,590,206. However, particles incorporating a combination of a β2agonist and a glucocorticosteroid have not been disclosed. Furthermore the size and the morphology of the particles obtained are not optimal for pulmonary delivery by inhalation.
The object of the invention is to provide a composition that is better adapted than products of the prior art, for delivery of a drug combination into the lungs.